104 research outputs found
Hamstrings and quadriceps muscle size and strength in female and male elite competitive alpine skiers
No full textOncogenic ALK F1174L drives tumorigenesis in cutaneous squamous cell carcinoma
No full textCutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer characterized by increased mortality. Here, we show for the first time that anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase of the insulin receptor superfamily, plays a pivotal role in the pathogenesis of cSCC. Our data demonstrate that the overexpression of the constitutively active, mutated ALK, ALK F1174L, is sufficient to initiate the development of cSCC and is 100% penetrant. Moreover, we show that cSCC development upon ALK F1174L overexpression is independent of the cell-of-origin. Molecularly, our data demonstrate that ALK F1174L cooperates with oncogenic Kras G12D and loss of p53, well-established events in the biology of cSCC. This cooperation results in a more aggressive cSCC type associated with a higher grade histological morphology. Finally, we demonstrate that Stat3 is a key downstream effector of ALK F1174L and likely plays a role in ALK F1174L-driven cSCC tumorigenesis. In sum, these findings reveal that ALK can exert its tumorigenic potential via cooperation with multiple pathways crucial in the pathogenesis of cSCC. Finally, we show that human cSCCs contain mutations in the ALK gene. Taken together, our data identify ALK as a new key player in the pathogenesis of cSCC, and this knowledge suggests that oncogenic ALK signaling can be a target for future clinical trials
Low-dose Rate Brachytherapy of the Prostate - a Therapeutic Option for Selected Patients with Localized Prostate Cancer
No full textMaking Nations, Creating Strangers: States and citizenship in Africa, edited by Sara Dorman, Daniel Hammett, and Paul Nugent
No full textLocalized and Locally Advanced Prostate Cancer: Treatment Options.
No full textBACKGROUND
There are many treatment options for localized and locally advanced prostate cancer with radiotherapy and surgery representing the main local therapeutic strategies.
SUMMARY
Depending on the risk of disease recurrence, we can stratify patients into low-, intermediate- and high-risk groups, which will guide patients' treatment. For low-risk patients, active surveillance is an option. Brachytherapy is also an option for low- and intermediate-risk patients and can be used as a boost following external beam radiotherapy for high-risk patients. For intermediate- and high-risk patients, radical prostatectomy and radiotherapy should be considered. Moreover, in addition to radiotherapy, concomitant androgen deprivation therapy may be needed. Finally, after radical prostatectomy and depending on pathological, biological and clinical factors, radiotherapy ± androgen deprivation therapy can be proposed as an adjuvant or salvage treatment. Key Messages: With radiotherapy and surgery being well-established treatment options for localized prostate cancer patients with equally good overall survival rates, priority must be given to patients' choice concerning the logistics and the toxicity profile of each option
Making Nations, Creating Strangers: States and citizenship in Africa, edited by Sara Dorman, Daniel Hammett and Paul Nugent. Leiden: Brill, 2007
No full textCOMBINATORIAL THEOREMS FOR THE CONSTRUCTION OF MODELS**These results were obtained while the author was working on a research project in the foundations of mathematics at the University of California, Berkeley, U.S. National Science Foundation Grant G-19673.
No full text
Interaction of vascular endothelial cells with CD8+ T-cells in vivo
No full textTransplantation of organs and cells saves and prolongs thousands of lives every year. Surgical techniques were significantly improved but major problems remain, in particular the host’s immune system. Despite advances in immunosuppressive therapies, chronic allograft rejection still occurs which is characterized by intimal thickening in the arteries and the replacement of graft parenchyma, a phenomenon called chronic transplant vasculopathy (CTV). Within three years after transplantation 45% of transplant patients are affected by CTV which leads to the failure of allografts of about 5% each year post transplantation. The reasons for its development and the mechanistic basis inducing CTV are still not clearly understood. In graft versus host disease (GVHD) and vascular rejection of solid organ transplants, vascular endothelial cells (EC) have been recognized as important targets for alloreactive cytotoxic T-lymphocytes (CTL) and the presence of CTL has been associated with CTV. Therefore, T-cell-mediated immunity and subsequent inflammation appear to be important features of the initiation and progression of CTV. The contribution of EC to CD8+ T-cell activation and therefore their role in the development of chronic vascular rejection is still controversially discussed. For that reason and the fact that after transplantation of vascularised organs EC are the first graft cells encountered by host lymphocytes, the detailed interaction of vascular EC with CD8+ T-cells has been assessed in vivo in the first part of our study, in order to find out whether EC are able to activate or tolerize naive CD8+ T-cells. Using a transgenic mouse model with beta-galactosidase (β-gal) expression confined to the vascular endothelium (Tie2-LacZ mice) and the help of β-gal TCR transgenic CD8+ T-cells (Bg1 mice), the capacity of EC presenting a minor histocompatibility antigen (mhAg) to induce a CD8+ T-cell response was studied. We could show that mhAg presentation on EC was ignored by CD8+ T-cells and was neither sufficient to activate nor to tolerize CD8+ T-cells. Moreover, the mhAg was cross-presented by BM-derived CD11c+ DC and led to spontaneous activation of β-gal-specific CD8+ T-cells in Tie2-LacZ mice. This identifies the priming of mhAg-specific CD8+ T-cells via DC as the critical step in the generation of alloimmune responses. Furthermore, no β-gal-specific CD8+ T-cell activation was induced after transplantation of fully vascularised heart or liver grafts from Tie2-LacZ mice into non-transgenic recipients confirming that CD8+ T-cell responses against mhAg cannot be initiated by EC.
In the second part of the study the major aim was to develop an experimental system that facilitates in vivo studies on the interaction of EC with activated CTL in a heart transplantation model. To this end, Tie2-LacZ hearts were heterotopically transplanted into C57BL/6 recipients. Tie2-LacZ hearts were accepted and showed no vascular inflammatory changes or neointima formation until day 100 post transplantation. Repetitive priming with β-gal peptide loaded DC induced a long-term β-gal-specific CTL response resulting in the induction of vascular inflammatory disease with neointima formation and vascular occlusion. Infection with β-gal recombinant mouse cytomegalovirus (MCMV-LacZ) however, led to a shorter activation of β-gal-specific CTL and thus to a less significant vascular inflammation in Tie2-LacZ hearts. Taken together, we suggest that it is the prolonged presentation of mhAg within secondary lymphoid organs that is responsible for the activation of EC-specific CTL and that activated CTL recognize thereafter mhAg specifically expressed on EC, leading to the development of chronic vascular rejection
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